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Various studies have indicated that the prevalence of depression is almost twice as high among women as among men. A major factor associated with the development of depression and other affective disorders are adverse and psychologically traumatic life events that contribute to changes in the neuroendocrine system, altering the capacity to adapt to stress. These changes are involved in the pathogenesis of mental disorders, along with genetic and other factors, and are to a significant degree regulated by gender dependent mechanisms. While women have a high prevalence of depressive disorders, men show a higher rate of alcohol and substance abuse. These differences in the epidemiology are most likely explained by different predisposition to mental disorders in men and women and a diversity of biological consequences to adverse life events. Taking this into account, there is a need for a critical review of currently used approaches to modeling depressive disorders in preclinical studies, including the use of animals of both sexes. Adaptation of experimental models and protocols taking into account gender characteristics of neuroendocrine changes in response to stress, as well as structural-morphological, electrophysiological, molecular, genetic and epigenetic features, will significantly increase the translational validity of experimental work.

Olfactory dysfunction is a serious symptom that requires careful differential diagnosis. The article presents convincing evidence that dysosmia is not only a symptom of rinological pathology, but also a manifestation of various neurodegenerative diseases. Some patients with SARS-CoV-2 have neurological symptoms. Modern studies show that olfactory and gustatory dysfunctions are significant symptoms in the clinical presentation of the COVID-19 infection. The importance of olfactory diagnostics in relatives of patients with hereditary neurodegenerative diseases for the purpose of early detection of pathology is noted. We consider the possibility of introducing new methods for the diagnosis of olfactory dysfunction, which is a promising task both in the field of neurology and otorhinolaryngology, in order to prevent the development of neurodegenerative diseases at an early stage, improve the quality of life and social adaptation of patients.

This review focuses on studies of pain threshold and tolerance in individuals with nonsuicidal self-injurious (NSSI) behavior. The data on methods of pain sensitivity studies are presented, with issues in animal modeling of NSSI discussed separately. The results of neuroimaging studies on pain sensitivity in individuals with NSSI are described, along with contribution of genetic factors, psychological variables, and disturbances in opioid and hypothalamic-pituitary-adrenal systems. A critical methodological analysis of the studies on pain sensitivity in individuals with NSSI was performed.

Over the past years, the prevalence of brain diseases and, consequently, their social significance and economic burden for society has been steadily increasing throughout the world. Brain diseases are a heterogeneous group of diseases that unite a number of disorders that are within the competence of both neurology and psychiatry, often concurrent or comorbid with each other. Z. P. Soloviev Research and Clinical Center for Neuropsychiatry is a leading medical organization in Moscow, which performs a full treatment cycle, studies the data and has postgraduate training programs in this field of medicine. It is conducting a number of relevant research programs; some in collaboration with international clinics. This study deals with the following programs: fundamental aspects of depression and stress-reactivity, suicidal and self-damaging behavior, usage of biofeedback and gravity therapy in rehabilitation and training programs for medical workers in successful communication.

In the model of induced neuronal resistance to the toxic effect of glutamate (deprivation of trophic factors), exosome secretion is demonstrated. Exosomes are secreted at the development of resistance during deprivation and at the first 24 h after preconditioning, as was shown by dot blot of extracellular fluid using anti-CD63 antibody. The autophagy inhibitor bafilomycin (0.01 μM) significantly reduces the quantity of the secreted exosomes at the stage of autophagy induction and at 24 h after induction. At the same time, inhibition of autophagy during the deprivation of trophic factors prevents the development of resistance, but inhibition of autophagy during the first 24 h after deprivation does not affect the development of resistance. We suggest that the long-term effects of preconditioning may be mediated by exosome secretion.

Background: Establishing the relationship between the damage in the neocortex and the functional manifestations of these lesions is important to understand the mechanisms of acute seizures and their consequences. An analysis of immediate seizures in patients with a traumatic brain injury (TBI) in practice is difficult, however it can be performed in animal models., Aim: To compare the damage to functional neocortical areas with the semiology of immediate seizures and behavioral disturbances in the acute period after lateral fluid percussion (TBI model) in rats., Material and Methods: The study was performed on 48 Wistar rats. TBI was modelled using lateral fluid-percussion injury to the right sensory-motor cortex. To study the semiology of immediate seizures, video recording was performed at the moment of the injury and 5 min after it. After that, a number of behavioral tests were employed., Results and Conclusion: This study presents the first detailed evaluation of damage to the functional neocortical areas in the acute period of TBI using the 'unfolded maps' approach. The focus of damage in the cortex increased from 3rd to 7th day and demonstrated a complex shape, extending far beyond the area of the direct impact. TBI induced immediate seizures with a variability which cannot be explained by the involvement of certain areas of the neocortex alone, as well as behavioral disturbances suggested to reflect developing necrosis predominantly in the sensory area of the neocortex.

Aim: To investigate gender differences in biochemical characteristics in patients with nonpsychotic mental disorders, and to study their association with childhood trauma., Material and Methods: Women (n=308) and men (92) between 18 and 45 years of age, without serious somatic comorbidities, were examined. Laboratory evaluation included markers of hypothalamic-pituitary-adrenal axis activity (cortisol), hypothalamic-pituitary-thyroid system (TSH), proinflammatory cytokines (Il-1β and Il-6) and the brain derived neurotrophic factor (BDNF). All participants underwent psychometric testing, which included the Child Abuse and Trauma Scale (CATS), Beck and Hamilton depression scale (HAM-D) and Spielberger Anxiety Inventory (STAI). Correlations were studied between the biochemical parameters and total CATS scores and severity of depression and anxiety in subgroups of women and men with a depressive disorder., Results and Conclusion: The men and women in the total study population significantly differed by representation of the different diagnostic classes, which was reflected by differing levels of depressive and anxiety symptoms. The main finding was a correlation between the level of childhood trauma and morning serum cortisol levels in men with depressive disorder, which was absent in women.

Aim: To analyze the pathological electrical activity during the acute period after traumatic brain injury (TBI) and to search for potential morphological correlates of this activity in the neocortex and hippocampus., Material and Methods: The study was performed on male Sprague Dawley rats. TBI was modeled using a lateral hydrodynamic impact in the sensorimotor cortex area. ECoG was continuously recorded one week before and one week after TBI. A histological analysis was performed one week after TBI. Brain slices were Nissl stained as well as immunohistochemically stained for astrocytes (GFAP) and microglia (Isolectin B4). The damage to the neocortex and hippocampus was evaluated., Results and Conclusion: The slowdown of the background activity one and six hours after TBI and appearance of epileptiform activity in a half of animals one week after TBI were shown. The number of discharges was correlated with the area of astrocyte gliosis in the neocortex and with the number of dark (ischemic-like) neurons in the hippocampus. Microglial activation did not correlate with the epileptiform activity. These data are important to understanding early mechanisms of post-trauma epileptogenesis.

The goal of treatment of brain pathologies may be regarded as re-establishment of optimal brain plasticity. Disturbances in neuroplasticity are associated with the appearance of multiple targets that should be subjects for pharmacological correction. Peptide hydrolysates derived from animal brain became a basis for multi-component organ-specific drugs which are widely used for treatment of cerebral pathologies. Potentially, the presence of many components in such drugs may be beneficial for simultaneous effects on different targets. In this article, new data are analyzed related to relevant molecular mechanisms underlying neuroprotective properties of cortexin. On a model of accelerated aging in rats, cortexin restored the ratio of pro- and antioxidative systems and demonstrated a significant anti-inflammatory effect both in the brain and at the systemic level. In in vitro experiments cortexin effectively and tissue-specifically inhibited brain caspase-8. Neuron-specific proteins β5-tubulin, creatine kinase B and protein 14-3-3 α/β were shown to be molecular partners of cortexin peptides in the brain. Thus, potential molecular mechanisms of cortexin neuroprotective effects are various and associated with key processes underlying neuroplasticity: signal transduction, energy metabolism, proteolytic protein modification, cell structure, as well as neuroinflammation. The pleiotropicity of mechanisms of cortexin action is based on the composition of the drug containing a variety of neuropeptides. The tissue specificity of these mechanisms determines to a significant degree the efficacy of the drug in treatment of cerebral pathologies.

Pharmacoresistance in epilepsy is an important problem from both clinical and fundamental perspectives. The existent hypotheses of pharmacoresistance are based on long term plastic rebuilding of the epileptic brain. One of potential mechanisms mediating such protracted changes are alterations of gene expression induced by epigenetic modifications of chromatin in brain cells of epileptic patients. Recently, changes in DNA methylation and histone post-translational modifications were reported in brain tissues of patients with pharmacoresistant epilepsy. Unfortunately, these data remain fragmentary and contradictory, therefore the results of animal models can partially fill this gap. The authors present a short review of the data concerning a potential role of epigenetic modifications in epilepsy.

Using temporal lobe epilepsy as an example, staging of long term plasticity in the hippocampus is considered. Major stages demonstrating opposite alterations in neuroplasticity are active epileptogenesis and the period of established temporal lobe epilepsy. During the epileptogenesis, multiple events resulting in forming of epileptic neuronal nets occur: changes in glutamatergic and GABAergic neurons, increase of aberrant neurogenesis, axonal sprouting and dendrite remodeling, particularly, supported by an excessive enhancement of the BDNF system in specific hippocampal regions. As epileptogenesis progresses, this stage of an aberrant superplasticity is changing for opposite events accompanying formation of the epileptogenic focus and limiting plasticity: axonal damage, neuronal cell death, hippocampal sclerosis, suppression of neurogenesis. At this neurodegenerative stage of temporal epilepsy, the inclusion of neuroprotectants with neurotrophic properties (e.g. drugs containing cerebral peptide hydrolizates) into the treatment protocol appears promising. Potential use of such neuroprotectants during the active epileptogenesis period is discussed.

Cortexin, a drug containing hydrolyzed brain peptides, has long been used in clinics, but the mechanisms of its action remain obscure. We have hypothesized that cortexin-related neuroprotection is associated with the ability of the drug to inhibit brain proteases. Cortexin effectively inhibited brain caspase-8, while its effects on caspase-1, -3, -9, cathepsin B and calpain were much less pronounced or absent. In addition, we isolated a peptide fraction from cortexin holding all the inhibitory capacity of the original drug, but with a much more simple composition. Both cortexin and its fraction prevented neuronal damage in a culture model of glutamate-induced cell death. Neuroprotective effect of Cortexin may be mediated by inhibition of the initiator caspase-8 in the brain.

One of the strategies to induce tolerance of neurons to toxic injury is preconditioning. Preconditioning is caused by a weak damage of cells, which become more resistant to subsequent, more severe damage. We found that preconditioning by deprivation of trophic factors, or deprivation of trophic factor and glucose effectively protects neurons against subsequent toxic effects of glutamate. Deprivation of trophic factors plays a decisive role in the development of resistance, regardless of whether it has been combined with glucose deprivation or not. Neuronal protection is achieved when the deprivation lasts from 30 min to two hours and is kept for a period of from one to five days. Preconditioning is accompanied neuronal secretion of cathepsin B occurs. We suggest that this phenomenon is associated with a more general process of exocytosis of lysosomes triggered by deprivation of trophic factors.

Opiate reinforcement is considered as a stimulus inducing addiction, however underlying neurobiological mechanisms remain obscure. According to the literature, BDNF (brain-derived neurotrophic factor) in the lateral ventral tegmental area (VTA) could modulate morphine reinforcement, but the role of BDNF in the midline VTA has not been studied yet. The aim of the study was to investigate the effect of a single intra-mid- line VTA injection on the acquisition and expression of morphine conditioned place preference (CPP). CPP procedure was composed of eight conditioning sessions (one session per day): morphine (i.p., 10 mg/kg) and saline injections were paired to the compartments and counterbalanced.Recombinant human BDNF (0.75 ug) or phosphate-buffered saline (PBS) as a vehicle were injected once into the midline VTA one day before or after conditioning. According to the CPP test rats spent more time in the morphine-paired compartments a scompared to the saline-paired compartments (p < 0.05). After a single BDNF injection into the midline VTA be- fore conditioning, but not after conditioning, differences in time spent in morphine and saline-paired compartments did not reach significance (p > 0.05). Thus, taking into account limitations of the results, we sug- gest that BDNF in the midline VTA may block morphine reinforcement.

We studied the effect of chronic combined stress (model of experimental neurosis) on behavior of rats with different basal strategies of behavior in novelty conditions. Chronic stress resulted in decreases in the body weight and testosterone contents in the blood and neocortex in all animals. Animals with initially low orient- ing-exploratory response in the "open field" test did not exhibit substantial alterations of behavior during repeated testing in this test of the "dark-light chamber" test; however, the depression-like behavior was more expressed in the second forced swim test. Chronic combined stress did not significantly affect the behavior of this group of rats. Animals with initially high orienting-exploratory response in the "open field" test exhibited decreased locomotor and exploratory activity in the repeated "open field" tests. The decreases in the locomotor and exploratory activity were substantially less expressed in the repeated tests in these rats after chronic combined stress. The indices of depression-like behavior increased one month after the end of exposure to chronic combined stress. Our data demonstrate that different responses to novelty in the "open field" test do not allow predict with reasonable certainty the development of depression-like behavior after exposure to chronic combined stress.

Though borderline psychiatric disorders (BPD) are quite common diseases, their pathogenesis remains obscure. Data from several groups and our previous results suggest that the pathological changes are typical not only for brain cells, but also for cells of the immune system. One of the evident illustrations of immune and nervous systems relationship in pathogenesis of mental diseases is the death of PBMC occurring in patients with depression. We have shown previously that activities of the caspases increase in some types of BPD. In this study, we have investigated caspase activities in PBMC of patients with BPD of different severity. It has been found that in severe depressive disorder activities of caspases were reduced either as compared to healthy controls or to patients with depression lesser severity. In contrast, in patients with severe anxiety activities of caspases were higher than in both control and patients with less severe forms of anxiety disorders. Thus, the study of caspase activity in PBMC makes it possible to differentiate between severe and mild forms of BPD.

The review considers possible mechanisms underlying large unpredictability of stress induced modulation of long-term synaptic plasticity. In studies of LTP, both increase and decrease can be observed dependently on stress paradigms, severity, duration, and period of recording, brain structure etc. Stress-induced glucocrti- coids release does not directly correlate with LTP changes, and corticosterone application in vivo andin vitro can either enhance or suppress LTP. The nature of stress induced modifications is usually explained by the balance between mineralocorticoid and glucocorticoid receptors, the later seems to provoke synaptic meta- plasticity rather than LTP disturbance, increasing the threshold of LTP induction. In addition, metaplasticity can be also modulated be many other neurotransmitters,'enhancing uncertainty and unpredictability of stress response, in particular because their action is highly regulated-by emotional experience.

The processes in the nervous and immune systems are closely interrelated. In particular, increased apoptosis was reported in lymphocytes of patients with depression. The aim of this study was to assess activities of proteases associated with cell death in lymphocytes of patient with personality disorders accompanied by depression and anxiety. In patients with personality disorders associated with organic brain dysfunction caspase activities were reduced in patients with depression and increased in patients with anxiety. The results may be useful for elucidation of pathogenetic mechanisms of personality disorders and in search of new biomarkers of these diseases.

In this theoretical study, the concept of connectome and connectopathy was used for the analysis of the data related to molecular mechanisms of the pathogenesis and comorbidities of neurological and psychiatric diseases (in particular, depression), as well as approaches to their pharmacotherapy. A scheme of main network levels underlying connectome is provided, including subcellular and molecular levels. Neuronal networks forming connectome are based on several 'lower' network levels, the state and interactions of these levels stipulating the state and functioning of the connectome as well as its dynamic changes. Similarly, network levels are demonstrated for connectopathies. Common network mechanisms of connectopathies, particularly depressive disorders and neurodegenerative diseases, are not only underlying the comorbidity, but also suggest common potential pharmacotherapeutic approaches.

Based on current clinical and classification concepts of suicidality, the biological parameters characteristic of suicidal behavior, completed and uncompleted suicides reported in the last few decades are discussed. The results obtained in the studies of neurotransmitter and other brain systems, immune system, lipid and other types of metabolism as well as data of neuroimaging brain studies and post-mortem investigation of brain structures are presented.

Analysis of the current state modeling of depression in animals is presented. Criteria and classification systems of the existing models are considered as well as approaches to the assessment of model validity. Though numerous approaches to modeling of depressive states based on disturbances of both motivational and emotional brain mechanisms have been elaborated, no satisfactory model of stable depression state has been developed yet. However, the diversity of existing models is quite positive since it allows performing targeted studies of selected neurobiological mechanisms and laws of depressive state development, as well as to investigate mechanisms of action and predict pharmacological profiles of potential antidepressants.

In the paper the role of philosophical approaches in analyses of the MRT data, neuropathologies is dis cussed. Importance of teleological approaches is stressed.

The data of epigenetic studies of stress reactivity and resilience in the pathogenesis of depression in experimental animals and humans subjected to stress at different periods of life are analyzed. Specific chromatin modifications, first of all histone acetylation and methylation, are controlling expression of definite genes in distinct brain structures. Epigenetic modulation of particular genes related to development of pro-depressive or antidepressive stress response are discussed (5HT transporter and receptors, corticotropin releasing hormone, glucocorticoid and their receptors, BDNF and other neurotrophic factors).

We studied the expression of mRNA for genes, whose protein products regulate the glutamate/NO/cGMP signal cascade in the frontal cortex, striatum, midbrain, and hippocampus of rats with various degrees of spontaneous morphine withdrawal syndrome. The concentration of Grin2a mRNA (subunit of the NMDA glutamate receptor) in the frontal cortex increased mainly in animals with severe abstinence. By contrast, the expression of mRNA for the Grin2b subunit in the striatum decreased in animals with mild abstinence. Variations in the content of mRNA for other products of the cascade (isoforms of NO-dependent guanylate cyclase and cGMP-dependent protein kinase) after morphine withdrawal were not related to the degree of abstinence. Our results suggest that the region-specific expression of mRNA for certain subunits of the NMDA glutamate receptor after morphine withdrawal can determine the degree of abstinence.

We studied the effects of afobazole on apoptosis through active caspase-3. Afobazole in a final concentration of 10(-8) M inhibits hyperactivation of effector apoptotic caspase-3 in HT-22 cell culture under conditions of glutamate toxicity.